CC BY
27A new player in psoriatic arthritis: a JAK inhibitor
Lazaros I. Sakkas
Mediterr J Rheumatol 2017; 28(4):210-1
mediterranean journal
of RHEUMATOLOGY
E-ISSN: 2529-198X
mediterranean journal of rheumatology December 2017 | Volume 28 | Issue 4
mediterranean journal 28
of RHEUMATOLOGY 2017
©Sakkas L I
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International L
COMMENTARY
A new player in psoriatic arthritis: a JAK inhibitor
Lazaros I. Sakkas
Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
Mediterr J Rheumatol 2017;28(4):210-1 https://doi.org/10.31138/mjn284.210
Article Submitted: 27/10/2017, Article Accepted 8/12/2017
Keywords: JAK, inhibitors, psoriatic arthritis, psoriasis.
Psoriatic arthritis (PsA) is an inflammatory arthritis in patients with psoriasis (Pso). Pso affects 2-4% of the general population while PsA affects 65% of Pso patients if one uses even regional imaging modalities.1,2 PsA can involve peripheral joints and spinal joints, causing oligoar-ticular or polyarticular arthritis and spondyloarthropathy, but also affects various tissues causing enthesitis, dac-tylitis, and uveitis. A radiographic characteristic of PsA, not found in rheumatoid arthritis (RA), is that it can cause bone erosions and bone formation at various joint sites. The pathogenesis of the disease is incompletely understood. Nevertheless, inflammatory cytokines, such as in-terleukin (IL)-12, IL-17, interferon (IFN)y, IL-23, and IL-22, and cells of the adaptive immunity and innate immunity are implicated. Moreover, the elevated cytokines of the IL-23/IL-17 axis with IL-17 and IL-22 of the axis having erosive and bone-forming actions, respectively, suggest that PsA and psoriasis may be the same disease.3 Recent recommendations for the treatment of PsA include non-steroidal anti-inflammatory drugs (NSAIDs), conventional synthetic disease-modifying antirheumatic drugs (DMARDs), phosphodiesterase 4 inhibitor (Apremilast), and biologicals, including tumour necrosis factor (TNF) inhibitors (TNFi), IL-17 inhibitors (secukinumab) and IL-
Corresponding author:
Lazaros Sakkas, MD, DM, PhD (London), FRCP (London)
Department of Rheumatology and Clinical Immunology
Faculty of Medicine
Biopolis, Larissa 41 110, Greece
Tel.: +302413502813
Fax: +302413501016
E-mail: lsakkas@med.uth.gr
ORCID ID: 0000-0002-7670-3314
IL-2, IL4, IL-15, IL-21
^yc-containing receptors
JAK1 JAK3
Type I IFN receptors
IL-10, IL-22
Type II cytokine receptors
JAK1 JAK1
IL-6, IL-11
gp130 containing receptors JAK1 JAK1
IFNy IFNy receptor
JAK2 TYK2
I
IL-12, IL-23 I
±
IL-12Rß1
2
JAK2 TYK2 l
Figure 1. Activation of cytokine pathways via JAKs.
12/IL-23 inhibitors (ustekinumab).4,5 A Janus kinase (JAK) inhibitor, tofacitinib, an oral agent approved for the treatment of RA, was used in either TNFi-naive or TNFi-expe-rienced PsA patients in two randomized controlled trials published in the October issue of New England Journal of Medicine.6,7 The Janus family kinases, JAK1, JAK2, JAK3 and TYK2, are cytoplasmic non-receptor protein kinases. As such, the phosphorylate tyrosine leave residues of their protein substrates. JAKs as homodimers or heterodimers bind to transmembrane receptors, activated by extracellular cytokines/growth factors, and activate downstream molecules, primarily the signal transducers and activators of transcription (STATs)8 (Figure 1).
210 Cite this article as: Sakkas L I. A new player in psoriatic arthritis: a JAK inhibitor. Mediterr J Rheumatol 2017;28(4):210-1
In a 12-month, double-blind, active controlled with adal-imumab, placebo-controlled, phase 3 trial, in patients with PsA and inadequate response to conventional synthetic DMARD, tofacitinib was used in a 5-mg twice daily dose, 10-mg twice daily dose, and adalimumab in a 40 mg biweekly dose. At month 3, placebo was blindly switched to 5 mg tofacitinib or 10 mg tofacitinib dose. Overall, there was no differences between the 5 mg dose, the 10 mg dose, and the adalimumab in efficacy across various aspects of the disease (peripheral arthritis, dactylitis, enthesitis, psoriasis) up to 12 months. In particular, at month 3, ACR20 was achieved by 50% in the 5-mg tofacitinib group, 61% in the 10 mg tofacitin-ib group, and 52% in the adalimumab group, and 33% in the placebo group. ACR50 was achieved by 28% in the 5-mg tofacitinib, 40% in the 10-mg tofacitinib, 33% in the adalimumab, and 10% in the placebo groups. However, during the study, infections - including herpes zoster, and cancer, excluding non-melanoma skin cancer - were increased in patients taking tofacitinib: this should be monitored closely in subsequent studies.6 In a second study, a 6-month, randomized, double-blind, placebo-controlled, phase 3 trial of patients with PsA and inadequate response to TNF inhibitors, tofacitinib was used in a 5 mg twice daily dose or 10 mg twice daily dose. At 3 months, placebo was blindly switched to 5 mg or 10 mg dose regimen. The ACR20, ACR50 and ACR70 response at 3 months and 6 months is shown in Table 1.7 As seen, at 3 months, the ACR50 response was superior in the tofacitinib group compared to placebo, but not the ACR70 response. To have a sense of comparison, in PsA patients with inadequate response to TNF inhibitors, at 6 months, the ACR20 response was achieved by ustekinumab, a IL-12/23 inhibitor, in 35.6% of patients vs 14.5% in the placebo group,9 and by secukinumab, an IL-17 inhibitor, in 45.5% of patients vs 14.3% in the placebo group.10 Infections, including herpes zoster, major adverse cardiovascular events, neu-tropenia, lymphopenia, and elevation of transaminases were observed in the tofacitinib group of patients and should be monitored in subsequent studies.
A NEW PLAYERIN PSORIATIC ARTHRITIS: A JAK INHIBITOR
In summary, a new player arrived in the courtyard of PsA. It appears to be effective, but requires vigilance for potential adverse effects.
CONFLICT OF INTEREST
The author declares no conflict of interest.
REFERENCES
1. Sakkas L I, Alexiou I, Simopoulou T, Vlychou M. Enthesitis in psoriatic arthritis. Semin Arthritis Rheum 2013;43:325-34.
2. Matthew A J, Bird P, Gupta A, George R E, Danda D. Magnetic resonance imaging (MRI) of the feet demonstrates subclinical inflammatory disease in cutaneous psoriasis patients without clinical arthritis. Ann Rheum Dis 2017;76:727.
3. Sakkas L I, Bogdanos D P. Are psoriasis and psoriatic arthritis the same disease? The Il-23/IL-17 axis data. Autoimmune Rev 2017;16:10-5.
4. Gossec L, Smolen J S, Ramiro S, de Wit M, Cutolo M, Dougados M, et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis 2016;75:499-510.
5. Coates L C, Kavanaugh A, Mease P J, Soriano E R, Laura Acos-ta-Felquer M, Armstrong A W, Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 Treatment Recommendations for Psoriatic Arthritis. Arthritis Rheumatol 2016;68:1060-71.
6. Mease P, Hall S, FitzGerald O, van der Heijde D, Merola J F, Avila-Zapata F, et al. Tofacinib versus adalimumab in psoriatic arthritis. New Engl J Med 2017;377:1537-50.
7. Gladman D, Rigby W, Azevedo V F, Behrens F, Blanco R, Kaszuba A, et al. Tofacitinib for psoriatic arthritis in patients with inadequate response to TNF inhibitors. New Engl J Med 2017;377:1525-36.
8. Ghoreschi K, Laurence A, O'Shea J J. Janus kinases in immune cell signaling. Immunol Rev 2009;228:273-87.
9. Richlin C, Rahman P, Kavanaugh A, McInnes I B, Puig L, Li S, et al. Efficacy and safety of the anti-IL-12/23 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapry:6-month, and 1-year results of the phase 3, multicenter, double-blind, placebo-controlled, randomized PSUMMIT 2 trial. Ann Rheum Dis 2014;73:990-9.
10. Kavanaugh A, McInnes I B, Mease P J, Hall S, Chinoy H, Kivitz A J, et al. Efficacy of subcutaneous secukinumab in patients with active psoriatic arthritis stratified by prior tumor necrosis factor inhibitor use: Results from the randomized placebo-controlled FUTURE 2 study. J Rheumatol 2016;43:1713-7.
Table 1. ACR20, ACR50 and ACR70 response of patients with PsA treated with tofacitinib at 3 months and 6 months.
ACR20 ACR50 ACR70
At 3 months
Tofacitinib 5 mg 50% 30% 17%
Tofacitinib 10 mg 47% 28% 14%
placebo 24% 15% 10%
At 6 months
Tofacitinib 5 mg 60% 38% 21%
Tofacitinib 10mg 49% 30% 14%
